Isolators are used in various industrial fields, for example in the chemical, pharmaceutical and nuclear industries but also in medicine in order to produce a volume which is separated from the surroundings and in which selected substances can be stored and manipulated, for example subjected to chemical reaction, wherein the transportation of material is prevented in (at least) one direction (from the isolator to the surroundings or else from the surroundings to the isolator). For instance, isolators used in the nuclear industry may be referred to as glove boxes, wherein a technician may reach into the box using a sealed glove to manipulate the contents therein without the atmosphere/material within the box leaking.
The prevention of the transportation of material from the isolator into the surroundings is necessary, for example, if radio-active substances or powderous chemicals are stored and handled in the isolator. Isolators in the nuclear field (i.e., glove boxes) are operated here under a high underpressure in order to prevent radio-active substances from escaping into the surroundings under all circumstances. On the other hand, in the case of chemicals a low underpressure compared to the atmospheric pressure is sufficient.
In contrast, a transportation of material from the surroundings into the isolator must be prevented, in particular in the case of isolators for aseptic pharmaceutical processes, in order to avoid contamination of the isolator volume or interior with germs from the surroundings. A relatively low excess pressure compared to the atmospheric pressure is already sufficient for this.
Handling of the substances in the isolator is preferably carried out in both cases using remote-controlled mechanical manipulators. However, there are a multiplicity of processes in which such automation is not possible, or is possible only at unacceptably high cost, with the result that it is not possible to dispense with human beings as the operator. The access of the operator to the interior of the isolator is carried out here by means of breakthroughs in the wall of the isolator, referred to as ports, which are equipped with flexible gloves which are clamped in a hermetically sealed fashion and are composed of a sufficiently resistant material. The gloves can, on the one hand, ensure the seal (integrity) of the isolator volume, but on the other hand they can also give the operator the necessary freedom of movement in order to carry out the necessary manipulations in the interior.
Any disruption of the integrity of the isolator entails economic or even health risks. If, for example, germs penetrate the isolator from the surroundings, an entire batch of aseptically manufactured pharmaceutical products may become unusable. If, in the inverse case, toxic substances escape from the isolator, they can endanger the operator and the surroundings. For this reason, such disruptions must be prevented in all cases and if they nevertheless occur despite all counter-measures, they must be detected and eliminated immediately.
Internationally recognized prescriptions such as, for example, the Guideline “Guidance for Industry—Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice” of the U.S. Food and Drug Administration (FDA), which is addressed specifically to the pharmaceutical industry and was updated in 2004, therefore recommends implementation of a comprehensive preventive maintenance programme. Gloves, seals, sealing means and also transfer systems should be subjected to daily testing. In addition, the actual period of use of all the critical components should be carefully logged in writing in order to ensure prompt replacement before the expiry of the permissible period of use.
The FDA Guideline pays particular attention to gloves. Damaged gloves or sleeves form contamination channels and constitute a critical breach of the integrity of the isolator. A preventive maintenance programme is recommended, said maintenance programme already starting with the selection of a particularly durable glove material and a data-based definition of the times of replacement of the glove. Whenever the gloves are used, they should be inspected visually for macroscopic defects. Physical integrity tests should be carried out routinely. The monitoring and maintenance programme should identify any glove with compromised integrity and initiate its replacement.
The FDA Guideline refers to the risk of a microbial migration through microscopic holes in gloves and to the lack of highly sensitive integrity tests for gloves and therefore recommends careful hygienic handling of the interior of the glove and the additional wearing of thin disposable gloves by the operator.
Within the territory of the EU, comparable regulations apply which were updated in 2008 and which are laid down in a German translation in the “Anhang 1 zum EG-Leitfaden der Guten Herstellungspraxis—Herstellung sterile Arzneimittel” [Annex 1 to the EC Guideline for Good Manufacturing Practice—Manufacturer of Sterile Medicines]. However, the recommendations contained therein regarding isolators do not go beyond the prescriptions of the FDA Guideline, and the latter can therefore be considered to be a generally valid standard.